It is known that diethyl .alpha.-acetyl-.alpha.'-methylsuccinate can be prepared in about sixty-three percent yield by reacting ethyl acetoacetate with ethyl .alpha.-bromopropionate in the presence of sodium hydroxide, potassium iodide and water. Chem. Abs. 62, 13037c abstracting (Zh. Pukl. Khim, 38(2), pp. 436-7 (1965). Also, J. Chem. Soc. (London), 4633-40 (1970) reports that this same diester can be prepared in about forty-seven percent yield by reacting ethyl acetoacetate with ethyl .alpha.-bromopropionate in the presence of sodium in ethanol. Similar disclosures are found at Chem. Abs. 54, 10852h; Chem. Abs. 49, 1565c of J. Chem. Soc. (London) 3313 (1953); and Chem. Abs. 38, 2332 of J. Ind. Chem. Soc., 20, 173-7 (1943).
David R. White, in the above-referenced application Ser. No. 938,972 and its predecessor application, described his findings that neither the aqueous basic system nor the ethanolic basic systems allowed the same alkylation to occur with the less expensive ethyl 2-chloropropionate in place of the ethyl 2-bromopropionate. He found that by using the 2-chloropropionate ester at moderate temperatures (40.degree.-50.degree. C.), no significant alkylation reaction was seen; under more vigorous (higher) temperature conditions, using these base systems, 2-chloropropionate and acetoacetate ester starting materials were consumed but little diethyl .alpha.-acetyl-.alpha.'-methylsuccinate ester accumulated in the product, evidencing that this valuable succinate ester intermediate is somewhat unstable and is further converted to undesired, useless by-products in those reaction mixtures.
The White application claims a process for preparing the diester of .alpha.-acetyl-.alpha.'-methylsuccinic acid comprising reacting an ester of acetoacetic acid with an ester of .alpha.-halopropionic acid wherein halo is chloro or bromo in a substantially anhydrous mixture of a nonpolar aprotic organic liquid having a dielectric constant below about 11 at 25.degree. C., e.g., toluene, at a temperature of from about 50.degree. C. to the reflux temperature of the mixture in the presence of a phase transfer agent, a catalytic amount of an iodide ion and a deprotonating base, e.g., potassium carbonate, having a surface area equivalent to a size below at least about 60 mesh, for a time sufficient to form the diester of the .alpha.-acetyl-.alpha.'-methylsuccinic acid. The above White applications are incorporated herein by reference for background and as an aid in describing elements used in this invention and distinctions therefrom.
Research on this and related chemical process steps to prepare ibuprofen from aliphatic starting materials continues. Somewhat surprisingly, it has been found according to this invention that the use of nonpolar, aprotic organic liquid of low dielectric constant, e.g., toluene, and the use of a deprotonating base of a particular particle size by Dr. White, is not necessarily the best way to obtain the highest practical yields of the necessary intermediate, the .alpha.-acetyl-.alpha.'-methylsuccinic acid ester. In my research I have raised the dielectric constant of the reaction mixture by adding a dipolar, aprotic liquid solvent and used larger particle size potassium carbonate than described by the White applications and come up with process improvements which not only raise the yields of the above succinate ester intermediate but have defined a process improvement which is more compatible with the chemical steps which follow toward the synthesis of the end product, ibuprofen.
For additional background to the use of .alpha.-acetyl-.alpha.-methylsuccinate esters in processes for preparing useful drug acid compounds, see British Pat. No. 1,265,800 and Belgian Pat. No. 820,267.